Innate Immune Response - Morgan Community College
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Transcript Innate Immune Response - Morgan Community College
The Innate Immune
Response
Chapter 15
Overview of Innate Defenses
First line of defense are
barriers that shield interior of
body from external
surroundings
Anatomical barriers include
skin and mucous membranes
Provide physical separation
Membranes bathed in
antimicrobial secretions
Overview of Innate Defenses
Sensor system signals when first line barriers
have been breached
Two important groups of receptors
Toll-like receptors and NOD proteins
Cell membrane proteins that recognize and bind to
families of compounds unique to microbes
nucleotide-oligomerization domains
Complement System
Overview of Innate Defenses
Toll-like receptors and
NOD proteins
Found on variety of
cells
Recognize families of
compounds
Enables cells to sense
invasion
Sends signal to body
to respond
Overview of Innate Defenses
Complement System
Acts in response to
stimuli
Activation sets off
chain reaction that
results in destruction
or removal of
invader
Overview of Innate Defenses
Phagocytes are specialized
cells that engulf and digest
microbes and cellular debris
Act as sentries
Alerted to signs of invasion
Release cytokine chemicals
More phagocytes can be
recruited from bloodstream
Attracted by chemical gradient
of the released cytokines
Phagocytosis movie
Overview of Innate Defenses
Cells of the immune system have an elaborate
communication system
Communication achieved through productions
of proteins
Proteins act as chemical messengers
Called cytokines
Cytokines from one cell diffuse to another
Bind to cytokine receptor on cell
Receptor transmits signal to cell interior
Induces changes in cellular activities
Overview of Innate Defenses
Inflammation is initiated by microbial invasion
or tissue damage
During inflammation cells in blood vessels
undergo changes that allow certain immune
particles to leak out of the blood
First Line of Defense
Physical barriers
Skin is most visible barrier
Covers majority of surfaces
in obvious contact with
environment
Mucous membranes
barrier that lines digestive
tract, respiratory tract and
genitourinary tract
Mucous protects these
surfaces from infections
First Line of Defense
Skin
Provides the most difficult barrier to penetrate
Composed of two main layers
Dermis
Contains tightly woven fibrous connective tissues
Makes extremely tough
Epidermis
Composed of many layers of epithelial cells
As cells reach surface become increasingly flat
Outermost sheets of cells embedded with keratin
Makes skin water repellent
Outer layers slough off taking microbes with it
First Line of Defense
Mucous membranes
Constantly bathed with mucus
Helps wash surfaces
Some mucous membranes have mechanisms
to propel microorganisms and viruses to areas
where they can be eliminated
First Line of Defense
Antimicrobial substances
Both skin and mucous membranes are protected by
variety of antimicrobial substances including
Lysozyme
Enzymes that degrades peptioglycan
Found in tears, saliva, blood and phagocytes
Peroxidase
Found in saliva, body tissues and phagocytes
Breaks down hydrogen peroxide to produces reactive oxygen
Lactoferrin
Sequesters iron from microorganisms
Iron essential for microbial growth
Found in saliva, some phagocytes, blood and tissue fluids
Defensins (Antibiotics)
Antimicrobial peptides inserted into microbial membrane
Found on mucous membranes and in phagocytes
First Line of Defense
Normal flora
Defined as microorganisms found growing on
body surfaces of healthy individuals
Not technically part of immune system
However, provides significant protection
Protects through competitive exclusion
Covers binding sites
Pathogens can’t bind
Completes for nutrients
Nutrients unavailable for pathogens
Cells of the Immune System
Always found in normal blood
Numbers increase during infection
Some cells play dual roles in both innate and
adaptive immunity
Blood cell formation called hematopoiesis
Blood cells including immune cells originate
from hematopoietic stem cells in bone marrow
Blood cells stimulated to differentiate by
colony-stimulating factor
Cells of the Immune System
General categories of blood cells
Red blood cells (RBC)
A.k.a erythrocytes
Carry oxygen in blood
Platelets
Fragments of megakaryocytes
Important component in blood clotting
White blood cells (WBC)
A.k.a leukocytes
Important in host defenses
Divided into four categories
Granulocytes
Dendritic cells
- Mononuclear phagocytes
- Lymphocytes
Cells of the Immune System
Granulocytes
Contain cytoplasmic
granuals
Divided into three types
Neutrophils
Basophils
Eosinophils
Cells of the Immune System
Neutrophils
Most abundant and important
in innate response
Sometimes called
polymorphonuclear
neutrophilic leukocytes
(PMNs)
Basophils
Involved in allergic reaction
Eosinophils
Important in expelling
parasitic worms
Active in allergic reactions
Cells of the Immune System
Mononuclear phagocytes
Constitutes collection of
phagocytic cells called
mononuclear phagocyte
system
Includes monocytes
Circulates in blood
Macrophages
differentiate from
monocytes
Present in most
tissues
Abundant in liver,
spleen, lymph
nodes, lungs and
peritoneal cavity
Cells of the Immune System
Dendritic cells
Branched cells
involved in adaptive
immunity
Functions as scout in
tissues
Engulf materials in
tissue and bring it to
cells of adaptive
immunity
Cells of the Immune System
Lymphocytes
Involved in adaptive
immunity
Two major groups
B lymphocytes
B cells
T lymphocytes
T cells
Another type
Natural killer
Lacks specificity of
B and T cells
Cell Communication
In order for immune system to respond cells
must communicate with environment and with
each other
Cell surface receptors are the “eyes” and
“ears” of the cell
Cytokines are the “voice”
Adhesion molecules act as the “hands”
Cell Communication
Surface receptors
Membrane proteins to which signal molecules
bind
Receptors specific to molecule to which it
bonds
Binding molecules called ligands
When ligand binds, receptor becomes
modified and send signal to cell
Cell responds by initiating some action
Cell Communication
Cytokines
Cytokines bind to surface receptors regulate cell function
Numerous cytokine classes
Chemokines = important in chemotaxis
Enhance ability of cells to migrate to appropriate site in body
Colony stimulating factors = important in multiplication and
differentiation of leukocytes
During immune response directs immature leukocytes to correct
maturation pathway
Interferons = important in control of viral infections
Also associated with inflammatory response
Interleukins = produced by leukocytes
Important in innate and adaptive immunity
Tumor necrosis factor = kill tumor cells
Instrumental in initiation of inflammation
Cell Communication
Adhesion molecules
Allows cells to adhere to each other
Responsible for the recruitment of phagocytes
to area of injury
Endothelial cells lining blood vessels produce
adhesion molecules that catch phagocytes as
they pass by
Causes phagocytes to slow and leak out of vessels
to area of injury
Sensor Systems
System within blood and tissue detect signs
of tissue damage or microbial invasion
Responds to patterns associated with danger
by
Directly destroy invading microbe
Recruiting other host defenses
Sensor Systems
Toll-like receptors (TLR) and NOD
proteins
Pattern recognition receptors
TLR allow cells to “see”
molecules signifying presence
of microbes outside the cell
TLR found in variety of cell
types
Recognize distinct “danger”
compounds
Signal is transmitted
Results in change of
gene expression of cell
NOD proteins do same for
inside cell
Sensor Systems
Complement system
Series of proteins circulating in blood and fluids
Augment activities of adaptive immune response
Stimulation of inactive proteins initiates cascade of
reactions
Circulate in inactive form
Results in rapid activation of components
Three pathways of activation
Alternative pathway
Lectin pathway
Classical pathway
Sensor Systems
Alternative pathway
Quickly and easily initiated
Relies on binding of
complement protein C3b to
cell surface
Initiates activation of
other compliment
proteins
Allows formation of
complement complex
C3b always circulating in
blood
Sensor Systems
Lectin pathway
Activation requires
mannan-binding lectins
(MBL)
Pattern recognition
molecules
Detect mannan
Polymer of mannose
Found in microbial
cells
MBL attaches to surface
Activates complement
proteins
Sensor Systems
Classical pathway
Activation requires
antibodies
Antibodies interact
with complement C1
Activates protein
Leads to
activation of all
complex
proteins
Sensor Systems
Complement
Complement system composed of nine proteins
C1 – C9
Numbered as discovered not order of activation
Certain proteins split into “a” and “b” fragments after
activation
C3 can spontaneously split to C3a and C3b
Insures enough C3b for activation of alternative pathway
Activation of complement leads to major protective
outcomes
Inflammation
Opsonization
Lysis of foreign cells
Sensor Systems
Inflammation
Complement components C3a and C5a
induce changes in endothelial cells
Effects vascular permeability associated with
inflammation
Opsonization
C3b binds foreign material
Allows phagocytes to easily “grab” particles
Sensor Systems
Lysis of foreign cells
Complexes of C5b, C6, C7,
C8 and multiple C9
spontaneously assemble
Forms donut shaped
structure called
membrane attack
complex (MAC)
Creates pores in
membrane
Most effective on Gramnegative cells
Little effect on Grampositive cells
Phagocytosis
Process of phagocytosis
Chemotaxis
Recognition/attachment
Use receptors to bind
invading microbes
Engulfment
Cells recruited to
infection
Phagocyte engulfs
invader forming
phagosome
Phagosome lysosome
fusion
Phagosome binds
lysosome forming
phagolysosome
Destruction and digestion
Organism killed due to
lack of oxygen and
decreased pH
Exocytosis
Phagocyte expels
material to external
environment
Inflammation
Inflammation occurs in
response to tissue damage
Four cardinal signs
Heat
Pain
Redness
Swelling
Loss of function
Fifth sign that can also be
present
Inflammation
Factors that initiate inflammatory response
Microbial products trigger toll-like receptors of
macrophages
Microbial cell surface can trigger complement
Causing release of pro-inflammatory cytokines
Leads to the production of C3a and C5a
Tissue damage results in enzymatic cascade
Cascades initiate inflammation
Inflammation
The inflammatory process
Initiation leads to a cascade of
events
Results in dilation of blood
vessels, leakage of fluid from
vessels and migration of
leukocytes and phagocytes
Leakage of phagocytes from
blood vessels called diapedesis
Certain pro-inflammatory
mediators cause the diameter of
blood vessels to increase
Resulting in increased blood
flow
Increased blood flow
responsible for cardinal signs of
inflammation
Inflammation
Outcomes of inflammation
Intent is to limit damage and restore function
Inflammation itself can cause considerable damage
Release of toxic products and enzymes from phagocytic
cell responsible for tissue damage
If inflammation is limited to area of injury damage
is usually nominal
If inflammation results in delicate systems
consequences are more sever
Inflammation around brain and spinal cord can lead
to meningitis
Inflammation
Apoptosis
Programmed cell death
Destroys cell without eliciting inflammatory
response
During apoptosis cells undergo changes to
signal macrophages
Cells are engulfed without triggering inflammatory
cascade
Fever
One of the strongest indicators of infection
Especially of bacterial infection
Important host defense mechanism
Temperature regulation center of body responds to
fever-inducing substances called pyrogens
Fever-inducing cytokines termed endogenous pyrogens
Microbial products termed exogenous pyrogens
Resulting fever inhibits growth of pathogens by
Elevating temperature above maximum growth
temperature
Activating and speeding up other body defenses